The broad, long-term goal of this application is to understand the molecular basis for cognitive impairment in Alzheimer's disease, in order to develop more effective therapies. The rationale for the experiments described below stems from our recent findings linking an aspect of cognitive decline in Tg2576 mice to the conversion of soluble to insoluble A-beta, and from our results showing improved behavioral performance following passive administration of A-beta antibodies. These observations have led us to propose that an intermediate of A-beta forming during the conversion of soluble to insoluble A-beta negatively influences cognitive function and can be neutralized with A-beta antibodies. For the sake of discussion in this application we refer to this entity as A.beta*. Using genetic and immune manipulations, we propose to test and extend the hypothesis that A.beta* causes cognitive impairment in Tg2576 and other mouse models of Alzheimer's disease. These results may provide important new information on the pathogenesis of dementia in Alzheimer's disease.